The primary objectives of this research project are to characterize a new immune checkpoint and to develop a new immunotherapeutic strategy to treat cancer. Immunotherapy that targets lymphoid cell checkpoints holds great promise for curing cancer. However, a majority of cancer patients do not respond to this form of therapy. In addition to lymphoid cells, myeloid cells play essential roles in controlling immunity to cancer. Whether myeloid checkpoints exist that can be targeted to treat cancer is not well established. Myeloid-derived suppressor cells (MDSCs) are a newly identified population of leukocytes important for cancer. Depletion of MDSCs leads to markedly enhanced anti-tumor immunity in mice, and may be crucial for the success of cancer immunotherapy in humans. Despite their significance in cancer, MDSCs remain to be the least understood subset of myeloid cells. It is unclear what transcriptional program specifies MDSC differentiation; it is unknown what pharmaceutical approach can be used to target MDSCs for the treatment of cancer. This grant application is inspired by our recent discovery that the transcription factor c-Rel is required for both human and murine MDSC development and/or function, and that c-Rel inhibitors are effective for treating cancer in mice. The goals of this project are to (i) elucidate the mechanisms through which c-Rel regulates murine and human MDSCs, and (ii) establish the efficacy and the mechanisms of action of our c-Rel inhibitors for the treatment of cancer.